The objective of the proposed research is to define the molecular mechanism of action of alpha-l-antitrypsin (AAT). AAT is a protein in human serum which inhibits many enzymes. Individuals who have a genetically determined severe deficiency in serum concentrations of AAT usually get pulmonary emphysema at an early age. This protein deficiency state is one of the few available clues to the biochemical nature of any form of emphysema. It is hoped that a clearer understanding of the function of AAT may lead to the following: l. Elucidation of the function of enzymes inhibited by AAT, and consequently the mechanism of emphysema production in patients with severe AAT deficiency. 2. Comprehension of the mechanism of disease production in patients with other forms of emphysema, if there are common features of the disease processes. 3. Availability of information which may permit the designing of drugs which could replace the function of AAT in deficient patients. The goals of the protocol will be approached by studying the interaction of purified AAT in vitro with purified enzymes specified conditions and with various specific modifications of the AAT or of the enzymes. BIBLIOGRAPHIC REFERENCES: Cohen, A.B.: The interaction of alpha-l-antitrypsin with chymotrypsin, trypsin and elastase. Biochem. Biophys. Acta, 391: 193-200, 1975. Cohen, A.B.: Chapter 8, Alpha-l-antitrypsin: A Systemic Determinant of Lung Structure and Function. In The Biochemical Basis of Pulmonary Function, Ed. by R. Crystal. A volume in the series: "Lung Biology in Health and Disease", Ed. by C. L'enfant. Marcel Dekker, Inc., New York, 1976.